The research proposal component of the application will evaluate the effects of both exogenous and endogenous agmatine in opioid-mediated events. Agmatine has been detected in mammalian central nervous system and found to antagonize NMDA receptors and inhibit nitric oxide synthase (NOS). Exogenously administered agmatine has also been shown to inhibit NMDA receptor/NOS-dependent behavior including chronic pain, and opioid tolerance and self-administration. These previous studies have been largely limited in terms of route of administration, dose-response, or pharmacodynamic evaluation. To determine the therapeutic window in which agmatine is effective for prevention of opioidergic events, exogenous agmatine will be administered centrally and systemically at varying time points in a model of spinal opioid analgesic tolerance as well as a model of opioid self-administration. Definition of the pharmacodynamic profile of exogenous agmatine in opioid-related behavior will advance our understanding of the therapeutic utility and endogenous role of this molecule. Elucidation of the role of the endogenous agmatine in opioid analgesic tolerance and drug abuse may lead to the identification of new therapeutic targets.